Heart failure (HF) is a progressive disease, affecting over 5 million individuals in the US alone, that is mediated in large part by increased neurohormone action at G protein-coupled receptors (GPCR). Inhibition of GPCR signaling with classical antagonists such as p-blockers can improve survival, but with varying degrees of success in different patient populations, thus alternative HF therapeutic strategies are needed. Arginine vasopressin (AVP) is a neurohormone that acts in the vasculature to modulate blood pressure and in the kidney to regulate water retention, but has also been shown to exert cardiac effects via the AVP type 1A receptor (VI AR). As with other neurohormones, AVP levels are elevated in patients with HF, which is associated with increased morbidity and mortality, and we have discovered that cardiac-specific V1 AR overexpression produces profound hypertrophy, fibrosis and failure, a process mediated through GOq protein-dependent signaling in the mouse heart. Conversely, we found that VI AR signaling though GPCR kinase (GRK)-dependent activation of extracellular-regulated kinase (ERK1/2) exerts survival effects. Thus, we hypothesize that although GOq protein-dependent V1 AR signaling can induce maladaptive hypertrophy and apoptosis, GRK-dependent VI AR signaling relays cardioprotective effects, the study of which will be the focus of Aim 1. Of clinical importance, many HF patients that are hospitalized due to acute exacerbation of their disease have their p-blocker therapy discontinued or reduced while at the same time may receive an AVP receptor antagonist to reduce hyponatremia secondary to high levels of AVP, which in some cases has been associated with increased mortality. There is currently no basic science or clinical data to guide physicians regarding these seemingly independent therapeutic interventions in terms of potential crosstalk. Our initial assessment of possible interactions between these GPCR systems showed that while AVP signaling significantly decreases the physiologic response to PAR agonists in isolated cardiomyocytes and in Langendorff-perfused hearts, VI AR stimulation results in enhanced recruitment of activated ERK1/2 to pi AR, which could promote protective signaling. Thus, we hypothesize that VI AR regulation of PAR signaling modulates cardiac function and survival, which will be the focus of Aim 2. The impact of VI ARdependent modulation of GRK- and pAR-dependent signaling on cardiac function and survival following cardiac injury will be the focus of Aim 3. Completion of these aims will enable us to establish a more rational approach to the development of novel HF strategies via selective or biased regulation of VI AR signaling.